Compounds containing aromatic hydroxyl functions such as polyhydroxy stilbenes are found in various plants and which have great importance as they exhibit excellent therapeutic properties such as use as antioxidants, platelet antiaggregants, anti-inflammatory or vasodilator, or as cell proliferative inhibitors.
The polyhydroxy stilbenes include Resveratrol ((E)-5-(4-hydroxystyryl)benzene-1,3-diol), Oxy resveratrol (4-[(E)-2-(3,5-Dihydroxyphenyl)ethenyl]benzene-1,3-diol), Piceatannol (5-[(E)-2-(3′,4′-dihydroxyphenyl)vinyl]benzene-1,3-diol) and Gnetol (2-[(1E)-2-(3,5-Dihydroxyphenyl)ethenyl]-1,3-benzenediol) of formulae:

In the synthesis of polyhydroxy stilbenes, the phenolic groups such as phenolic —OH must be protected in the form of ether derivatives in order to decrease the acidity of the phenolic hydrogens. The phenolic —OH groups can be protected by different protecting groups selected from methyl, methylene, isopropyl, t-butyl, acyl, benzyl or tetrahydropyranyl (THP) and the like. Once the phenolic group is protected as an ether, reactions could be performed on the molecule; finally the ether must be deprotected to release the parent phenolic —OH. Several deprotection methods have been described in the literature; however they suffer from one disadvantage or another.
Several methods have been described for deprotection of phenolic ethers. For example, phenolic methyl ethers have deprotected to remove the methyl moiety using hydrogen halide such as hydrogen chloride or hydrogen bromide under highly acidic conditions; highly colored products formed in these reactions. In addition the phenolic compounds react further with the halogen compounds used thus setting a major drawback on this route. In the case of benzyl ethers, deprotection is carried out by catalytic hydrogenation, which results, in the specific case stilbene derivatives; the carbon-carbon double bond may get hydrogenated.
U.S. Pat. No. 6,844,471, U.S. Pat. No. 7,253,324 and Tetrahedron Lett. 32, 10, 1991, 1321-24 discloses Lewis acids-aromatic amine for deprotection of phenolic ethers such as benzyl, allyl or alkyl ethers, particularly in the preparation of resveratrol and piceatannol. However, the aromatic amines used are expensive, highly toxic and difficult to remove.
PCT publication No. WO 2009/043761 (“the '761 publication”) discloses a process for the synthesis of stilbene derivatives by deprotection of corresponding ethers using aluminium chloride-aliphatic tertiary amine such as triethylamine or tributylamine in chlorobenzene.
Other Lewis acids such as boron tribromide/boron trichloride etc have been disclosed in U.S Patent publication No. 2005/240062, Tetrahedron Lett., 44, 1 (2003), 193-198 and Tetrahedron, 59 (2003), 3315-3321 for deprotection of phenolic methyl, benzyl or isopropyl ethers. In these Lewis acids very low temperatures are required to perform the reaction, which in turn inconvenience of performing such reactions in larger commercial scale. Moreover, boron tribromide/boron trichloride, are expensive reagents which are unsafe to use industrially.
CN Patent No. 1663939 discloses a demethylation process of phenolic methyl ethers for the preparation of resveratrol by using aluminium chloride-pyridine system at temperature of 165° C. to 170° C. The use of toxic pyridine solvent and reaction at higher temperatures are not appropriate selection for industrial large scale process.
Accordingly, there remains a need for an alternative process for preparation of polyhydroxy stilbenes, particularly for the purpose of the synthesis of resveratrol and its analogues, which is simple and cost effective.
The present invention provides a process for the preparation of polyhydroxy stilbenes by using simple and commercially available deprotecting agents such as Lewis acid-Secondary amines that are away from the aforementioned difficulties. The process of the present invention can be practiced on an industrial scale, and also can be carried out without sacrifice of overall yield.